Angiotensin receptor blockers for the treatment of covid-19: pragmatic, adaptive, multicentre, phase 3, randomised controlled trial

Dear Editor

The association of ACE2 receptors and SARS-CoV-2 has perplexed scientists and clinicians since the beginning of the Pandemic. An obvious question comes to mind if we are able to block the receptor with available effective blockers, the virus should find no channels to enter into the cells. But no such results were forthcoming in a number of studies. The above study is also one of such kind drawing similar inferences over a larger population.

It was later postulated that blocking the ACE-2 by ARBs rather leads to the opening of dormant receptors or overexpression of receptors in nearby places but the studies using ARB or ACE inhibitors failed to demonstrate any worsening of symptoms in Covid-19.

It was inferred that patients being treated with ACEIs and ARBs should continue to use them for approved indications without any proactive additions or deletions provoked by Covid-19.

Should we not challenge the narrative set in relation to SARS-CoV-2 Virus and the ACE-2 receptor? Molecular studies have shown that the main receptor for SARS-CoV-2 binding is angiotensin-converting enzyme II (ACE-2). However, successful entry of the virus into host cells depends on not only the attachment of the virus to the ACE2 but also the simultaneous activation of type II transmembrane serine protease TMPRSS2 enzyme which cleaves and activates the virus spike (S) protein.

Also, as per Human Protein Atlas, the ACE2 receptor is abundantly expressed in the gut, kidneys, and testis, and in relatively lower levels in the lungs and heart. However, the lungs and heart are implicated as the main target organs of SARS-CoV2 infection while testicles are relatively spared. In nutshell, though SARS-CoV-2 infection can lead to multi-organ failure there has been no direct correlation between the abundance of ACE2 receptors in an organ and clinical complications.

Should it not lead to research into the other receptors of viral entry?

References:
1.Sriram, K., & Insel, P. A. (2020). Risks of ACE Inhibitor and ARB Usage in COVID‐19: Evaluating the Evidence. Clinical Pharmacology and Therapeutics, 108(2), 236-241. https://doi.org/10.1002/cpt.1863
2. Felordi, M. S., Memarnejadian, A., Najimi, M., & Vosough, M. (2021). Is There any Alternative Receptor for SARS-CoV-2? Cell Journal (Yakhteh), 23(2), 247-250. https://doi.org/10.22074/cellj.2021.7977
3. Singh, R., Rathore, S. S., Khan, H., Bhurwal, A., Sheraton, M., Ghosh, P., Anand, S., Makadia, J., Ayesha, F., Mahapure, K. S., Mehra, I., Tekin, A., Kashyap, R., & Bansal, V. (2022). Mortality and Severity in COVID-19 Patients on ACEIs and ARBs—A Systematic Review, Meta-Analysis, and Meta-Regression Analysis. Frontiers in Medicine. https://doi.org/10.3389/fmed.2021.703661
4. Lopes RD, Macedo AVS, de Barros E Silva PGM, et al. Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial. JAMA. 2021;325(3):254–264. doi:10.1001/jama.2020.25864
5. Gong J, Sun Y, Xie L. ACEI/ARB Drug Therapy in COVID-19 Patients: Yes Or No? J Transl Int Med. 2021 Mar 31;9(1):8-11. doi: 10.2478/jtim-2021-0011. PMID: 33850795; PMCID: PMC8016358.